The overall objective of this proposal will be to characterize humoral immune responses induced in vivo during chronic HIV2 and SIV infection in man and monkeys which correlate with protective immunity or which limit disease progression. To do this we will produce and characterize large panels of human and rhesus monkey monoclonal antibodies (HMAbs and RhMAb) which reflect in vivo B cell recognition of envelope glycoprotein epitopes that elicit neutralizing antibody responses in chronically infected patients and monkeys. Particular emphasis will be placed on generation of neutralizing MAbs from Rhesus monkeys which have been infected with attentuated live SIV vaccines, as these animals resist challenge with pathogenic SIV strains and do not develop disease. Since HIV-2 and SIVmac and SIVmn strains belong to the same group of lentivruses and share many epitopes, it is likely that neutralizing epitopes in these viruses will be similar; however, it is uncertain whether the repertoire or function of neutralizing antibodies in each host will identical. By producing and characterizing both human and rhesus MAbs which are reactive with SIV/HIV2 glycoproteins, we will have a unique opportunity to compare humoral responses at the monoclonal antibody level during chronic infections in humans and non-human primates. While murine MAbs can identify a variety of neutralization epitopes, it is impossible to predict that infected hosts will recognize the same epitopes. Since rhesus and human MAbs are representative antibody responses to infection, they may provide better guides to effective vaccine design.